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Multiparametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer

ABSTRACT: Metastasis occurs frequently after resection of pancreatic cancer (PaC). We hypothesized that multiparametric analysis of pre-metastatic liver biopsies will classify patients according to their metastatic risk, timing, and organ site. Liver biopsies obtained during pancreatectomy from 49 patients with localized PaC and 19 control patients with non-cancerous pancreatic lesions were analyzed combining metabolomic, tissue and single cell transcriptomics, and multiplex imaging approaches. Patients were followed prospectively (median three years) and classified into four recurrence groups; early (<6 months post resection) or late (>6 months post resection) liver metastasis (LiM), extrahepatic (EHM) metastasis, and disease-free survivors (NED). Overall, PaC livers exhibited signs of augmented inflammation, compared to controls. Enrichment of neutrophil extracellular traps (NETs), Ki-67 upregulation, and decreased liver creatine significantly distinguished those with future metastasis from NED. Patients with future LiM were characterized by scant T cell lobular infiltration, less steatosis, and higher levels of citrullinated H3, compared to patients who developed EHM metastasis, who had overexpression of interferon target genes (MX1, NR1D1) and an increase of CD11B+ NK cells. Upregulation of sortilin-1 and prominent NETs, together with the lack of T cells and a reduction in CD11B+ NK cells, differentiated patients with early-onset from those with late-onset LiM. Liver profiles of NED closely resembled those of controls. Using the above parameters, a machine learning-based model was developed that successfully predicted the metastatic outcome at the time of surgery with 78% accuracy. Therefore, multiparametric profiling of liver biopsies at the time of PaC diagnosis may determine metastatic risk and organotropism, and guide clinical stratification for optimal treatment selection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE267209 | GEO | 2024/06/28

REPOSITORIES: GEO

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Project description:Background: Liver metastasis is the major cause of death following a diagnosis of colorectal cancer (CRC) and is a major health burden. Most molecular studies of CRC have profiled primary tumor samples and not the metastasis samples. In this study, we compared the copy number profiles of matched primary and liver metastatic CRC to better understand how the genomic structure of primary CRC differs from the metastasis. This has important implications for whether it is justified to base therapeutic approaches solely on data from the primary tumour. Methods: Paired primary and metastatic tumours from 16 patients and their adjacent normal tissue samples were analyzed using Single-Nucleotide-Polymorphism (SNP) arrays to determine copy number alterations. Nine patients had a synchronous liver metastasis at the time of CRC diagnosis and 7 patients developed a liver metastasis metachronously. Genome-wide chromosomal copy number alterations were assessed, with particular attention to 189 genes known to be somatically altered in CRC and 25 genes that are clinically actionable in CRC. These data were analyzed with respect to the timing of primary and metastatic tissue resection and with exposure to chemotherapy. Results: The genomic divergence with the whole genome duplication correction applied the average percent copy number discordance across all pairs of samples was 22.02%. The pairs of tumour samples collected prior to treatment revealed a significantly higher copy number differences compared to previously treated liver metastasis samples (P=0.024). However, loss of heterozygosity (LOH) acquired in metastasis was significantly higher in previously treated liver metastasis samples compared to treatment naïve liver metastasis samples (P= 0.0064) and which included where KRAS mutation was present in the primary cancers but was not detectable in the metastatic sample following chemotherapy. With regard to 25 genes that are clinically actionable in CRC, amplification of the genes ERBB2, FGFR1, CDK8 or PIK3CA was observed in the metastatic tissue of 4 patients but not in the matched primary CRC. In these cases, knowledge of these metastatic specific alterations could have informed therapeutic decision making and may have improved patient outcome. Conclusion: Intra-patient genomic discrepancies observed between primary and metastatic tissue

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Multiparametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer

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